Résumé
In many tumors, the increased biosynthesis and growth required for tumor progression is achieved by metabolic reprogramming associated with the activation of specific oncogenes. This can manifest itself as a shift to aerobic glycolysis coupled with increased anabolic metabolism or altered catabolism. This is especially relevant to tumors with activated Myc, in which Myc-Max heterodimers are transcriptional mediators of biosynthesis and growth. Work from many labs has implicated Myc in multiple aspects of the shift to increased glucose and glutamine uptake and stimulation of mitochondrial biogenesis and activity. Importantly, Myc-Max does not function alone, but within the context of an extended transcriptional network comprised of the Max-binding, Myc-antagonizing Mxd proteins as well as the Max-like protein, Mlx, and its heterodimerization partners MondoA and ChREBP (also known as MondoB) In order to understand how functional interactions and dependencies within the network influence Myc's role in normal and neoplastic cell behavior, we examined cell growth after siRNA mediated knockdown (KD) of different Max and Mlx network members in a panel of c-Myc and N-myc inducible cell lines. Results showed a synthetic lethal interaction between high level of Myc expression and loss of MondoA, or its heterodimeric binding partner Mlx. This synthetic effect was observed both in tissue culture and in mouse xenografts. By employing transcriptomic and metabolomic analyses we show that the MondoA-Mlx arm of the extended Max-Mlx network is required for deregulated Myc to drive metabolic reprograming and maintain survival and growth of these tumor cell. We further show that a subset of Myc-induced genes involved in metabolism require MondoA for full expression. Interestingly, knockdown of a number of these genes alone, which control a variety of metabolic pathways, can recapitulate the synthetic lethal interaction with deregulated Myc. Taken together, these data suggest that both Myc-Max and MondoA-Mlx complexes coordinately regulate the transcriptional activity of a group of genes critical for Myc's ability to reprogram tumor metabolism. The integration of Myc and MondoA functions may serve to link Myc to nutrient sensing and to augment metabolic flexibility within the evolving tumor. PC and DD contributed equally to this work. This research supported by NIH/NCI grant R37CA57138. Citation Format: Patrick A. Carroll, Daniel Diolaiti, Lisa McFerrin, Michelle Hulrich, Pei Feng Cheng, Haiwei Gu, Danijel Djukovic, Daniel Raftery, Robert N. Eisenman. Synthetic lethal interactions between members of the extended MYC network during metabolic reprograming in MYC-driven cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B30.